Anticholinesterase Agents For Alzheimer's Disease Treatment: An Updated Overview.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease that compromises the cognitive system and causes dementia. In general, AD affects people over 65 years old, which implies a social impact if we consider future projections due to the increase in life expectancy. The drugs currently marketed only slow the progression of the disease. In this sense, the search for new drugs is a relevant topic in medicinal chemistry. The therapeutic strategy adopted herein is the cholinergic hypothesis, for which acetylcholinesterase enzyme (AChE) inhibitors constitute the main treatment for the disease. OBJECTIVE: This review compiles research in synthetic and natural compounds with AChE inhibitory function. METHODS: Data were collected based on investigations of AChE inhibitors in the last 5 years of the 2010 decade. Synthetic and natural compounds were investigated, for which Ligand Based Drug Design (LBDD) and Structure Based Drug Design (SBDD) strategies were performed to better understand the structure-activity relationship of promising therapeutic agents. RESULTS: Prediction of physicochemical and pharmacokinetic properties used to calculate the bioavailability radar, lipophilicity, drug-likeness, and pharmacokinetics parameters (SwissADME) indicated that most active compounds are associated with the following characteristics: molecular weight above 377 g/mol; molar refractivity over 114; fraction Csp3 below 0.39 and TPSA above 43 Å2. The most active compounds had a lipophilicity parameter in the range between 2.5 and 4.52, a predominating lipophilic character. Atoms and bonds/interactions relevant for drug development were also investigated and the data pointed out the following tendencies: number of heavy atoms between 16 and 41; number of aromatic heavy atoms between 6 and 22; number of rotatable bonds between 1 and 14; number of H-bond acceptors between 1 and 11; number of H-bond donors below 7. Molecular docking studies indicated that all compounds had higher Goldscores than the drugs used as a positive control, indicating a stronger interaction with the enzyme. CONCLUSION: The selected compounds represent a potential for new anticholinesterase drugs and may be good starting-point for the development of new candidates. Also, design rules can be extracted from our analysis.

Novel trypanocidal thiophen-chalcone cruzain inhibitors: structure- and ligand-based studies.

Background: Chagas disease is a neglected tropical disease that affects millions of people worldwide and for which no effective treatment is available. Materials & methods: 17 chalcones were synthesized, for which the inhibition of cruzain and trypanocidal activity were investigated. Results: Chalcone C8 showed the highest cruzain inhibitory (IC50 = 0.536 µm) and trypanocidal activity (IC50 = 0.990 µm). Molecular docking studies showed interactions involving Asp161 and the thiophen group interacting with the S2 subsite. Furthermore, quantitative structure-activity relationship (q2 = 0.786; r2 = 0.953) and density functional theory studies were carried out, and a correlation between the lowest unoccupied molecular orbital surface and trypanocidal activity was observed. Conclusion: These results demonstrate that these chalcones are worthwhile hits to be further optimized in Chagas disease drug discovery programs.

Efficient Fabrication of Organic Electrochemical Transistors via Wet Chemical Processing.

A wet processing method to fabricate high-performance organic electrochemical transistors (OECTs) is reported. Wet chemical processing enables a simple and reliable patterning step, substituting several complex and expensive cleanroom procedures in the fabrication of OECTs. We fabricate depletion-mode OECTs based on poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) and enhancement-mode OECTs based on a conjugated polyelectrolyte PCPDTBT-SO3K on rigid and flexible substrates using this wet processing method. We show that the wet chemical processing step can also serve as a chemical treatment to enhance the electrical properties of the active material in OECTs. To highlight the potential of the fabrication process in applications, a transistor-based chemical sensor is demonstrated, capable of detecting methylene blue, a popular redox reporter in biodetection and immunoassays, with good detectivity. Given the tremendous potential of OECTs in emerging technologies such as biosensing and neuromorphic computing, this simple fabrication process established herein will render the OECT platform more accessible for research and applications.

Antioxidant Activity, Molecular Docking, Quantum Studies and In Vivo Antinociceptive Activity of Sulfonamides Derived From Carvacrol.

The synthesis and antioxidant, antinociceptive and antiedematogenic activities of sulfonamides derived from carvacrol-a druglike natural product-are reported. The compounds showed promising antioxidant activity, and sulfonamide derived from morpholine (S1) demonstrated excellent antinociceptive and antiedematogenic activities, with no sedation or motor impairment. The mechanism that underlies the carvacrol and derived sulfonamides' relieving effects on pain has not yet been fully elucidated, however, this study shows that the antinociceptive activity can be partially mediated by the antagonism of glutamatergic signaling. Compound S1 presented promising efficacy and was predicted to have an appropriate medicinal chemistry profile. Thus, derivative S1 is an interesting starting point for the design of new leads for the treatment of pain and associated inflammation and prooxidative conditions.

Liquid-Liquid Phase Separation of Tau Driven by Hydrophobic Interaction Facilitates Fibrillization of Tau.

Amyloid aggregation of tau protein is implicated in neurodegenerative diseases, yet its facilitating factors are poorly understood. Recently, tau has been shown to undergo liquid liquid phase separation (LLPS) both in vivo and in vitro. LLPS was shown to facilitate tau amyloid aggregation in certain cases, while being independent of aggregation in other cases. It is therefore important to understand the differentiating properties that resolve this apparent conflict. We report on a model system of hydrophobically driven LLPS induced by high salt concentration (LLPS-HS), and compare it to electrostatically driven LLPS represented by tau-RNA/heparin complex coacervation (LLPS-ED). We show that LLPS-HS promotes tau protein dehydration, undergoes maturation and directly leads to canonical tau fibrils, while LLPS-ED is reversible, remains hydrated and does not promote amyloid aggregation. We show that the nature of the interaction driving tau condensation is a differentiating factor between aggregation-prone and aggregation-independent LLPS.